Levalbuterol salt

ABSTRACT

Levalbuterol L-tartrate affords crystals possessing properties desirable for use in a metered dose inhaler.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional patentapplication No. 60/432,195 filed on Dec. 10, 2002, the disclosure ofwhich is incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] Levalbuterol (also known as (R)-albuterol) is a beta agonistuseful as a relaxant of smooth muscle tissue, for example in thetreatment of bronchospasm in patients suffering from asthma or chronicobstructive pulmonary disease. It is commercially available as a salt,levalbuterol hydrochloride, in a solution formulation adapted foradministration by inhalation using a nebuliser and is sold in the UnitedStates under the brand name XOPENEX™. A process for the preparation oflevalbuterol hydrochloride is described in U.S. Pat. No. 5,545,745. Ithas been found that crystals of levalbuterol hydrochloride obtained bythis process are plate-like in shape and possess properties generallyundesirable in a product intended for administration using a metereddose inhaler.

[0003] It would be desirable to administer levalbuterol using a metereddose inhaler (MDI).

[0004] The particles of active ingredients for delivery into the lungsof patients using an MDI must meet some very demanding criteria. Thepatient must be able to receive reproducible doses of a safe andeffective amount of the particles deep into the lungs. Thus, theparticles of the active ingredient must be of a stable, microscopic sizewithin an acceptable distribution range. In particular, they must beresistant to agglomeration into larger particle clusters, and must notchange in size or morphology during storage under varying conditions oftemperature and relative humidity or in the presence of formulationcomponents, such as carriers or propellants. Preferably they should havean aerodynamically favorable shape, such as a fiber (Crowder T. M., etal., Pharmaceutical Research, Vol. 19. No. 3, March 2002).

SUMMARY OF THE INVENTION

[0005] The present invention provides levalbuterol L-tartrate, includinglevalbuterol L-tartrate specifically in crystalline form; a process forpreparing levalbuterol L-tartrate in crystalline form; a pharmaceuticalcomposition comprising levalbuterol L-tartrate, including levalbuterolL-tartrate specifically in crystalline form; a metered dose inhalercomprising a canister containing an aerosol formulation of levalbuterolL-tartrate in crystalline form; and a method of affectingbronchodilation in a patient using levalbuterol L-tartrate, includinglevalbuterol L-tartrate specifically in crystalline form.

DETAILED DESCRIPTION OF THE INVENTION

[0006] A novel salt of levalbuterol has now been found that can beobtained in a crystalline form possessing properties particularlydesirable in a particulate product to be formulated for administrationby inhalation.

[0007] According to one aspect, therefore, the present inventionprovides levalbuterol L-tartrate.

[0008] Levalbuterol L-tartrate is a hemitartrate; that is to say itcontains half a mole of L-tartaric acid per mole of levalbuterol.

[0009] It has been found that levalbuterol L-tartrate can be obtained inthe form of needle-like crystals that possess particularly advantageousproperties. Thus, the crystals have been found to be relativelyresistant to agglomeration when micronized and, unlike crystals of thehydrochloride salt, to possess excellent stability, both as bulk drugand in the presence of aerosol formulation components, such as ethanol.They therefore provide a means for delivering effective, reproducibledoses of aerosolized levalbuterol from a metered dose or dry powderinhaler into the lungs of patients requiring treatment.

[0010] The crystals have been prepared from (R)-benzylalbuterol by theprocess described hereinafter in Example 1. It has been found that theselection of (R)-benzylalbuterol as the starting material for theprocess, and the particular process conditions selected all effect thequality and properties of the crystals formed. However, persons skilledin the art will appreciate that alternative processes may be devised forproducing crystals having properties essentially equivalent to those ofthe product of Example 1.

[0011] According to another aspect therefore, the present inventionprovides levalbuterol L-tartrate in crystalline form.

[0012] The crystals obtained by the process of Example 1 have been foundto be needles of approximate dimensions 10-50 microns in length and 0.2to 4 microns in width (by microscopic examination), and to contain verylow levels of residual substances. The ethanol content (from thecrystallization solvent) was found to be about 0.5% by weight afterdrying.

[0013] Particles of active ingredients for administration by inhalationdesirably have an aerodynamic diameter of from 1 to 10 microns,preferably from 1 to 5 microns. If necessary, the size of particlesobtained by crystallization may conveniently be reduced bymicronization.

[0014] According to another aspect, therefore, the present inventionprovides levalbuterol L-tartrate in micronized form.

[0015] It has been found that crystals containing a reduced (0.3%)ethanol content do not readily afford a stable particle sizedistribution after micronization.

[0016] According to another aspect, therefore, the present inventionprovides levalbuterol L-tartrate crystals containing at least 0.3%, forexample at least 0.4% ethanol, such as from 0.4 to 0.7% ethanol,preferably from 0.4 to 0.5%.

[0017] Drug substances are generally administered to patients inpharmaceutical compositions.

[0018] According to another aspect, therefore, the present inventionprovides a pharmaceutical composition, which comprises levalbuterolL-tartrate as described herein, together with a pharmaceuticallyacceptable carrier.

[0019] The pharmaceutical composition according to the invention may beadapted for administration to patients by any convenient route, such asby oral, mucosal (e.g. nasal, sublingual, vaginal, buccal or rectal),parenteral or transdermal administration. It may be in the form of, forexample, a solution, suspension, powder, tablet, aerosol formulation,lozenge, suppository, emulsion, hard or soft gelatin capsule or syrup.The levalbuterol tartrate may be dissolved in the carrier, diluted bythe carrier or supported by the carrier. Thus the carrier may be asupport for the levalbuterol tartrate, such as a capsule, sachet, paperor other pharmaceutical container.

[0020] Preferably, the pharmaceutical composition is an aerosolformulation adapted for administration using a metered dose inhaler, theaerosol formulation comprising levalbuterol L-tartrate in crystallineform and a propellant.

[0021] The propellant may be any suitable propellant used in aerosolformulations, for example, a hydrofluoroalkane (HFA), such as1,1,1,2-tetrafluoroethane (HFA134) or 1,1,1,2,3,3,3-heptafluoropropane(HFA227). HFA134 is preferred. The propellant may comprise at least 90%by weight of the aerosol formulation.

[0022] The aerosol formulation may further comprise a surfactant. Thesurfactant serves to stabilize the levalbuterol L-tartrate in asuspension, and may also serve as a valve lubricant in the metered doseinhaler. It may be any suitable surfactant used in aerosol formulations.Examples of surfactants used in aerosol formulations are described inU.S. Pat. No. 5,225,183, which is hereby incorporated by reference. Apreferred surfactant is oleic acid. The surfactant, when present, maygenerally be present in an amount of from 1:100 to 1:10surfactant:levalbuterol L-tartrate, preferably about 1:20.

[0023] The aerosol formulation may further comprise a co-solvent. Afunction of the co-solvent in the aerosol formulation is to facilitatedissolution of the surfactant, which may have poor solubility in thepropellant. It may be any suitable carrier used in aerosol formulations.A preferred co-solvent is ethanol, especially dehydrated ethanol. Thecontent of ethanol may conveniently be up to 10% by weight of theaerosol formulation, such as from 2 to 6%.

[0024] Metered dose inhalers comprise a canister containing an aerosolformulation, a metering valve and a valve stem. In use, a patientdepresses the valve stem and inhales, causing a dose of the formulationto be administered and taken into the patient's lungs.

[0025] According to a further aspect, therefore, the present inventionprovides a metered dose inhaler comprising a canister containing anaerosol formulation as described herein, a metering valve and a valvestem.

[0026] Preferably the interior surface of the canister is coated, forexample with a protective polymer. The inhaler preferably has anaperture with a diameter in the range of from 0.25 to 0.58 mm, morepreferably from 0.25 to 0.48 mm, such as from 0.30 to 0.36 mm.

[0027] In one embodiment, the present invention provides a metered doseinhaler containing an aerosol formulation substantially as described inExample 3 herein. The safety and efficacy of levalbuterol tartrateadministered using such a metered dose inhaler has been evaluated inclinical trials in comparison with Proventil HFA™. Proventil HFA™ is thetrade name of a product sold by Schering Corporation in the UnitedStates. It is a metered dose inhaler containing racemic albuterolsulfate (i.e. containing a 1:1 mixture of (R)-albuterol and(S)-albuterol). The results of the clinical trials showed thatadministration of 90 μg of levalbuterol tartrate afforded the sameefficacy as 180 μg of racemic albuterol sulfate. However, surprisingly,levalbuterol tartrate was found to give 5-20% lower systemic exposure(blood levels) of (R)-albuterol in adults compared with albuterolsulfate, and 30-40% lower exposure in children (ages 4-11). Systemicexposure to (R)-albuterol is undesirable, because the compound causesside effects associated with its activity as a beta agonist, and theseside effects increase with increasing systemic exposure. The sideeffects include changes in serum potassium levels, elevated glucoselevels and cardiovascular effects, such as increased heart beat rate.Accordingly, it is believed that levalbuterol tartrate provides aparticularly advantageous vehicle for delivering (R)-albuterol topatients, especially to children.

[0028] In another embodiment, the pharmaceutical composition is in theform of a dry powder suitable for inhalation or insufflation. Thecomposition may comprise levalbuterol L-tartrate crystals alone (e.g.having an aerodynamic diameter of from 1 to 10 microns, preferably from1 to 5 microns), or levalbuterol L-tartrate blended or spray driedtogether with a suitable pharmaceutically acceptable carrier. Suitablepharmaceutically acceptable carriers include, without limitation,solvates of one or more natural or synthetic carbohydrates, such as amonosaccharides, disaccharides, trisaccharides, oligosaccharides,polysaccharides, polyols, amino acids and proteins, and/or in the formof their pharmaceutically acceptable esters, acetals, or salts (wheresuch derivatives exist). The carrier is preferably lactose, morepreferably lactose monohydrate. The dry powder composition may bepresented in unit dosage form in, for example, capsules or cartridges ofe.g. gelatin, or blister packs from which the powder may be administeredwith the aid of an inhaler or insufflator. The dry powder compositionmay be presented in multi dose form metered with the aid of an inhaleror insufflator.

[0029] Conveniently, dry powder formulations are administered usingmultidose dry powder inhalers.

[0030] The present invention therefore also provides a multidose drypowder inhaler, comprising a dry powder reservoir containing a drypowder aerosol formulation of levalbuterol L-tartrate as describedhereinabove, and a metering chamber.

[0031] According to another aspect, the present invention provides aprocess for the preparation of levalbuterol L-tartrate, which comprisescombining a solution of levalbuterol with a solution of L-tartaric acidand recovering levalbuterol L-tartrate crystals.

[0032] Preferably the solvent in each solution comprises ethanol. Thesolvent may be, for example, ethanol denatured with 5% methanol.

[0033] When the solvent in each solution comprises ethanol, the solutionof levalbuterol is preferably combined with the solution of L-tartaricacid at a temperature in the range of from 47 to 65° C., more preferablyfrom 48 to 60° C., especially from 50 to 53° C. It has been found thatcrystals formed from ethanol at a temperature above 60° C. (afterdrying) have a low ethanol content (less than 0.3%), whereas thoseformed at a temperature below 47° C. (after drying) have a high ethanolcontent (greater than 0.5%). Conveniently the solution of L-tartaricacid is added to the solution of levalbuterol gradually, for exampleover a period of from 1 to 3 hours, while maintaining the temperaturewithin the preferred range. The resultant mixture is then allowed tocool, then the crystals are recovered, spread out on a tray and driedunder vacuum at a temperature of about 35 to 40° C. It has been foundthat crystals according to the invention exhibit good stability atelevated temperatures with regard to dimer formation when compared withcrystals of the sulfate salt; the commercial salt of racemic albuterolbeing the sulfate.

[0034] Levalbuterol L-tartrate is a hemitartrate. Hence, in preparingthe crystals, preferably one mole of levalbuterol should be combinedwith half a mole of L-tartaric acid. The concentration of levalbuterolin the solution of levalbuterol is preferably in the range of from 0.38to 0.43 moles per liter, such as from 0.38 to 0.42 moles per liter. Theconcentration of L-tartaric acid in the solution of L-tartaric acid ispreferably in the range of from 0.94 to 1.06 moles per liter, such asfrom 0.96 to 1.03 moles per liter.

[0035] The process conditions are preferably selected so as to providecrystals having a median length of 10 to 50 microns and a median widthof 0.2 to 4 microns.

[0036] Preferably the levalbuterol L-tartrate has been prepared byhydrogenating R-benzylalbuterol in the presence of palladium on carbon.Crystals prepared starting from levalbuterol that has been prepared fromR-benzylalbuterol in this way have been found to be of high purity.

[0037] In general, the hydrogenation may be performed at a temperaturein the range of from 20 to 45° C., preferably from 30 to 35° C., such asfrom 33 to 37° C. A convenient solvent is ethanol (commerciallyavailable ethanol is ethanol denatured with 5% methanol). Thehydrogenation is preferably conducted under conditions selected toeffect conversion of at least 99.9% of the R-benzylalbuterol withoutover reduction of other functional groups. The palladium on charcoalused preferably contains up to 0.33 wt % palladium. The reaction mixtureis stirred or agitated during the hydrogenation.

[0038] (R)-benzylalbuterol may be obtained by the process described inU.S. Pat. No. 5,545,745.

[0039] According to another aspect, the present invention provides amethod of effecting bronchodilation in a patient in need of treatment,which comprises administering an effective amount of levalbuterolL-tartrate.

[0040] Preferably micronized crystals of levalbuterol L-tartrate areadministered to the patient by inhalation using a metered dose inhaler.

[0041] The patient may be a human or a non-human mammal, such as a dog,cat, horse, cow, sheep or pig. Preferably, the patient is a human.

[0042] The amount of levalbuterol L-tartrate administered will dependupon many factors, such as the species, weight and age of the patient,and the severity of the condition to be treated. For example, a doseadministered to a human using a metered dose inhaler may contain from 25to 120 μg of levalbuterol (calculated as the free base), such as 45 or90 μg.

[0043] According to another aspect, the present invention provideslevalbuterol L-tartrate, for use in therapy.

[0044] According to yet another aspect, the present invention providesthe use of levalbuterol L-tartrate in the manufacture of a medicamentfor use as a bronchodilator.

[0045] According to a still further aspect, the present inventionprovides a pharmaceutical composition comprising levalbuterol L-tartrateand a pharmaceutically acceptable carrier for use as a bronchodilator.

[0046] Although the foregoing invention has been described in somedetail for purposes of illustration, it will be readily apparent to oneskilled in the art that changes and modifications may be made withoutdeparting from the scope of the invention described herein.

[0047] The following Examples illustrate the invention.

EXAMPLE 1

[0048] Preparation of Levalbuterol L-Tartrate in Crystalline Form

[0049] In the following, ethanol refers to the commercially availablesolvent, which is ethanol denatured with 5% methanol.

[0050] L-tartaric acid (4.11 kg) and ethanol (21.9 kg) were charged to afirst reactor. The contents of the reactor were then agitated at atemperature in the range of from 20 to 25° C. to form a clear solution.The solution was then kept until it was used.

[0051] (R)-Benzylalbuterol (18.0 kg) and 10% palladium on carbon (50%water wet, 60 g) were charged to a suitable pressure reactor. Theatmosphere of the reactor was then evacuated and replaced three timeswith nitrogen to exclude air. Under vacuum, ethanol (48.1 kg) was added,with agitation of the contents of the reactor. The atmosphere of thereactor was again evacuated and replaced three times with nitrogen toexclude air. Then, the atmosphere was pressurized to 50 psig (3.4 bar)with nitrogen and vented. After venting, the atmosphere was pressurizedto 50 psig (3.4 bar) with hydrogen, then vented, and then once againpressurized to 50 psig (3.4 bar) with hydrogen. The temperature was thenadjusted into the range of from 33 to 37° C., and the mixture was thenagitated in this temperature range. The progress of the reaction wasmonitored at approximately one hour intervals until the reaction wascomplete [after 4.5 hours, the content of (R)-benzylalbuterol was0.09%].

[0052] The hydrogen was then vented from the pressure reactor, and theatmosphere in the reactor was pressurized with nitrogen to 50 psig (3.4bar) and vented three times. The contents of the reactor were thencooled to a temperature in the range of from 19 to 25° C., and thenfiltered through a 3 μm and 0.3 μm in-line cartridge filter into a glasslined reactor. Ethanol (59.3 kg) was then added, affording anapproximately 11% by weight solution of levalbuterol. The solution wasthen heated to a temperature in the range of from 47 to 53° C.

[0053] The contents of the first reactor (a solution of L-tartaric acid)were then filtered through a 3 μm polishing filter and charged to theglass-lined reactor containing the levalbuterol over a period of 120minutes. During this time, a precipitate formed. The first reactor wasthen rinsed with ethanol (6.17 kg), and the contents charged to theglass-lined reactor containing the precipitate. The contents were thenagitated at 47 to 53° C. for 63 minutes, then cooled linearly to 19 to25° C. over 128 minutes.

[0054] Approximately one third of the contents of the reactor wereseparated using a centrifuge. The product was then washed with ethanol(13.2 kg) and then again with ethanol (12.5 kg). The wet product (9.99kg) was then discharged from the centrifuge.

[0055] Approximately one half of the remaining contents of the reactorwere separated using the centrifuge. The product was then washed withethanol (13.4 kg) and then again with ethanol (12.4 kg). The wet product(10.29 kg) was then discharged from the centrifuge.

[0056] The remaining contents of the reactor were then separated usingthe centrifuge. The product was then washed with ethanol (12.8 kg) andthen again with ethanol (12.6 kg). The wet product (9.86 kg) was thendischarged from the centrifuge.

[0057] The combined wet product was then loaded into a vacuum tray dryerand was dried at 35-40° C. for 21 hours to afford 16.51 kg oflevalbuterol L-tartrate as needle-like crystals containing 0.49%ethanol. The crystals generally had a length of about 10-50 microns, awidth of about 0.2 to 4 microns and an aspect ratio of about 20:1.

EXAMPLE 2

[0058] Micronization of Levalbuterol L-Tartrate Crystals

[0059] Levalbuterol L-tartrate crystals obtainable by the process ofExample 1 were de-lumped by manual screening. The screened material wasthen micronized using a 4-inch (10.16 cm) pancake-style fluid energymill with a venturi pressure of 50 psi (3.45 bar) and a mill pressure of100 psi (6.895 bar). The mill operator used a vibratory feeder to supplythe unmicronized levalbuterol L-tartrate to the mill at a rate of1.4±0.4 kg per hour.

[0060] The resultant product consisted of crystalline needles comprisingsmaller needles (0.5 to 3 μm in length) with aspect ratios between 3:1and 10:1, longer needles (3 to 9 μm in length) with aspect ratios ofapproximately 15:1, and fine particle fragments of approximately 0.5 μm.

[0061] The needle-like form of the particles in the micronized productis a typical of particles in a micronized product, which are usuallymore uniformly spherical in character. Needle-like particles aredesirable in a product intended for administration by inhalation, due totheir aerodynamic properties.

EXAMPLE 3

[0062] Metered Dose Inhaler Formulations of Levalbuterol L-TartrateCrystals Amount per Can Amount per Gram (45 μg/ (90 μg/ (45 μg/ (90 μg/Component actuation)* actuation)* actuation)* actuation)* Levalbuterol15.6 mg 31.3 mg 1.04 mg 2.08 mg L-tartrate Oleic Acid NF 0.7815 mg 1.563mg 0.0521 mg 0.104 mg Dehydrated 0.7140 g 0.7140 g 0.0476 g 0.0475 gethanol USP HFA 134a 14.28 g 14.28 g 0.951 g 0.950 g Total 15.01 g 15.03g 1.00 g 1.00 g

[0063] The formulation is prepared following a conventional procedure,for example as described below.

[0064] A portion of the requisite amount of dehydrated ethanol(approximately 94%) is added to a suitable tared formulation vesselpreviously flushed with filtered nitrogen. Oleic acid is added to theformulation vessel containing the dehydrated ethanol with the aid of adehydrated ethanol rinse as needed to ensure quantitative transfer. Abase mixer (approximately 250 rpm) is started, and the batch ishomogenized for about 1 minute. The vessel and contents are then chilledto about 2-6° C. The speed of the base mixer is then reduced toapproximately 100 rpm and micronized levalbuterol L-tartrate is addedcarefully to the vessel. The base mixer is then returned toapproximately 250 rpm and the batch is homogenized for about 10 minutes.The remainder of dehydrated ethanol is then added to the batch to reachthe required weight, followed by stirring for about 10 minutes at about250 rpm. The vessel and contents are then chilled (2-6° C.), and thistemperature is maintained throughout the subsequent filling process.

[0065] The concentrate suspension (e.g. 0.730±0.022 grams per can) isthen filled into aluminum canisters having an interior coating ofHOBA8666 (a pigmented epoxy phenolic resin available from HOBA, Lackeund Farben GmbH, Postfach 115772407, D-72411, Bodelhausen, Germany), anda valve is applied. The valve is crimped into place with an appropriatecollet crimper. HFA 134a is then pressure-filled through the valve (e.g.14.28 grams per can) using a positive piston filler with a suitableadapter. All units are stored (valve down orientation) for three days,followed by weight checking to remove units with gross leakage.

[0066] The canister is loaded into a standard metered dose inhaleractuator available from Bespak Europe, King's Lynn, Norfolk, PE30 2JJ,United Kingdom, having an aperture with a diameter in the range of from0.30 to 0.36 mm.

[0067] Stability Study

[0068] A stability study has been conducted on batches of 45 μg and 90μg per actuation products prepared as described above. The results areas follows:—

[0069] 25° C./60% RH, valve orientation up

[0070] 25° C./60% RH, valve orientation down

[0071] 40° C./75% RH, valve orientation up

[0072] 40° C./75% RH, valve orientation down

[0073] The results are tabulated below.

[0074] 25/60 valve up TEST INITIAL 1-MONTH 3-MONTH 6-MONTH ParticleSize - 1.9 2.0 2.0 1.9 Andersen Cascade Impactor MMAD (μm) (Average)Particle Size - 1.7 1.7 1.7 1.6 Andersen Cascade Impactor GSD (Average)Particle Size - 31.6% 34.5% 32.5% 34.1% Andersen Cascade Impactor fpf(Average) Emitted Dose 41.1 mcg 42.0 mcg ¹46.1 mcg ¹45.9 mcg Uniformity(5.0%) (2.7%) (3.1%) (2.3%) Average (RSD)

[0075] 25/60 valve down TEST INITIAL 1-MONTH 3-MONTH 6-MONTH ParticleSize - 1.9 1.9 2.0 1.8 Andersen Cascade Impactor MMAD (μm) (Average)Particle Size - 1.7 1.7 1.7 1.5 Andersen Cascade Impactor GSD (Average)Particle Size - 31.6% 32.9% 32.9% 34.6% Andersen Cascade Impactor fpf(Average) Emitted Dose 41.1 mcg 42.2 mcg ¹46.8 mcg ¹47.1 mcg Uniformity(5.0%) (4.7%) (3.5%) (3.5%) Average (RSD)

[0076] 40/75 valve up TEST INITIAL 1-MONTH 3-MONTH 6-MONTH ParticleSize - 1.9 2.0 2.0 1.9 Andersen Cascade Impactor MMAD (μm) (Average)Particle Size - 1.7 1.8 1.7 1.6 Andersen Cascade Impactor GSD (Average)Particle Size - 31.6% 31.6% 32.8% 34.3% Andersen Cascade Impactor fpf(Average) Emitted Dose 41.1 mcg 41.9 mcg ¹47.3 mcg ¹48.1 mcg Uniformity(5.0%) (3.4%) (3.3%) (3.3%) Average (RSD)

[0077] 40/75 valve down TEST INITIAL 1-MONTH 3-MONTH 6-MONTH ParticleSize - 1.9 2.1 2.1 2.0 Andersen Cascade Impactor MMAD (μm) (Average)Particle Size - 1.7 1.8 1.6 1.6 Andersen Cascade Impactor GSD (Average)Particle Size - 31.6% 31.6% 33.5% 33.7% Andersen Cascade Impactor fpf(Average) Emitted Dose 41.1 mcg 40.5 mcg ¹48.0 mcg ¹51.0 mcg Uniformity(5.0%) (3.2%) (3.3%) (2.4%) Average (RSD)

[0078] Particle Size Definitions

[0079] Aerodynamic Diameter—The diameter of a unit-density sphere havingthe same terminal settling velocity as the particle in question. It isused to predict where in the respiratory tract such particles willdeposit.

[0080] Aerodynamic (equivalent) diameter—diameter of a unit-densitysphere having the same gravitational-settling velocity as the particlein question. 1 Aerodynamic diameter takes into account the shape,roughness, and aerodynamic drag of the particle. Used for movement ofparticles through a gas.

[0081] Cascade impactor—a device that uses a series of impaction stageswith decreasing particle cut size so that particles can be separatedinto relatively narrow intervals of aerodynamic diameter; used formeasuring the aerodynamic size distribution of an aerosol.

[0082] Geometric standard deviation—(GSD)— A measure of dispersion in alognormal distribution (always greater than or equal to 1.0).

[0083] Mass median aerodynamic diameter—(MMAD)— The geometric meanaerodynamic diameter. Fifty percent of the particles by weight will besmaller that the MMAD, 50% will be larger.

[0084] Fine particle fraction—(fpf)—a proportion of the emitted dosecollected on stages 3 to filter of an Anderson Cascade impactor.

[0085] Relative standard deviation—(RSD)

REFERENCES

[0086] 1-Aerosol Measurement: Principles, Techniques and Applications.Edited by Klaus Willeke and Paul A. Baron. Van Nostrand Reinhold, N.Y.,1993.

[0087] 2-Fundamentals of Aerosol Sampling. Gregory D. Wight. LewisPublishers, CRC Press, 1994

[0088] Comparison of the Solubility of Levalbuterol L-Tartrate Crystalswith that of Levalbuterol Hydrochloride Crystals in HFA 134/EthanolBlends Actual Day Day Day Day Day Active Ethanol 1 2 4-5 6-8 57-65 Salt% μg/g μg/g μg/g μg/g μg/g Tartrate 0.00 NA 0.00 0.02 0.12 2.01 0.070.10 0.44 1.18 5.28 0.69 0.94 1.81 2.97 9.80 1.65 2.32 5.30 6.82Hydrochloride 0.00 0.08 1.13 0.33 4.20 2.16 4.45 5.01 5.25 10.57 5.2530.93 31.89 36.54 41.07 10.16 127.78 132.92 134.15 151.96

[0089] The results show that levalbuterol L-tartrate has substantiallylower solubility in ethanol than levalbuterol hydrochloride. Thisproperty is desirable in crystals to be used in the preparation of anaerosol formulation adapted for use in a metered dose inhaler, becausesuch formulations are commonly prepared by combining micronized crystalswith ethanol (as a co-solvent), then adding the propellant (which wouldforce any dissolved product back out of solution, potentially causingcrystal growth).

1. Levalbuterol L-tartrate.
 2. Levalbuterol L-tartrate as claimed inclaim 1, which is in crystalline form.
 3. Levalbuterol L-tartrate asclaimed in claim 2, containing from 0.3 to 0.7% ethanol.
 4. LevalbuterolL-tartrate as claimed in claim 2, which is in micronized form. 5.Levalbuterol L-tartrate as claimed in claim 4, which is in the form ofneedle-like particles.
 6. A pharmaceutical composition, which compriseslevalbuterol L-tartrate as claimed in claim 1, together with apharmaceutically acceptable carrier.
 7. A pharmaceutical composition asclaimed in claim 6, which is an aerosol formulation adapted foradministration using a metered dose inhaler, the aerosol formulationcomprising levalbuterol L-tartrate in crystalline form and a propellant.8. A pharmaceutical composition as claimed in claim 7, in which thepropellant is 1,1,1,2-tetrafluoroethane.
 9. A pharmaceutical compositionas claimed in claim 7, which further comprises a surfactant.
 10. Apharmaceutical composition as claimed in claim 7, which furthercomprises a co-solvent.
 11. A pharmaceutical composition as claimed inclaim 10, in which the co-solvent is ethanol.
 12. An aerosol formulationadapted for administration using a metered dose inhaler, the aerosolformulation comprising levalbuterol L-tartrate crystals in the form ofmicronized, needle-like particles, and a propellant.
 13. An aerosolformulation as claimed in claim 12, in which the propellant is1,1,1,2-tetrafluoroethane.
 14. An aerosol formulation as claimed inclaim 13, which further comprises from 2 to 6% by weight of ethanol as aco-solvent.
 15. A metered dose inhaler comprising a canister containingan aerosol formulation as defined in claim 7, a metering valve and avalve stem.
 16. A metered dose inhaler comprising a canister containingan aerosol formulation as defined in claim 12, a metering valve and avalve stem.
 17. A pharmaceutical composition as claimed in claim 6,which is adapted for administration using a dry powder inhaler orinsufflator.
 18. A process for the preparation of levalbuterolL-tartrate crystals, which comprises combining a solution oflevalbuterol with a solution of L-tartaric acid and recoveringlevalbuterol L-tartrate crystals.
 19. A process as claimed in claim 18,in which the solvent in each solution comprises ethanol.
 20. A processas claimed in claim 18, in which the crystallization conditions areselected so as to provide crystals having a length of 10 to 50 micronsand a width of 0.2 to 4 microns.
 21. A process as claimed in claim 18,in which the levalbuterol L-tartrate has been prepared by hydrogenatingR-benzylalbuterol in the presence of palladium on carbon.
 22. A processas claimed in claim 21, in which the hydrogenation has been conductedunder conditions selected to effect conversion of at least 99.9% of theR-benzylalbuterol without over reduction of other functional groups. 23.A process as claimed in claim 18, in which the crystals are dried andmicronized, the crystallization and drying conditions being selected soas to afford needle-like particles after micronization.
 24. A processfor the preparation of levalbuterol L-tartrate crystals, which comprisescombining a solution of levalbuterol with a solution of L-tartaric acid,recovering levalbuterol L-tartrate crystals, and then drying andmicronizing the recovered crystals, the crystallization and dryingconditions being selected so as to afford needle-like particles aftermicronization.
 25. Levalbuterol L-tartrate crystals whenever obtained bythe process of claim
 18. 26. Levalbuterol L-tartrate crystals wheneverobtained by the process of claim
 24. 27. A method of effectingbronchodilation in a patient in need of treatment, which comprisesadministering to said patient an effective amount of levalbuterolL-tartrate.
 28. A method as claimed in claim 27, in which micronizedcrystals of levalbuterol L-tartrate are administered by inhalation usinga metered dose inhaler.
 29. A method as claimed in claim 28, in whichthe micronized crystals of levalbuterol L-tartrate are in the form ofneedle-like particles.